Novel Monotherapy in Recurrent H3 K27M–Mutant Diffuse Midline Glioma

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In an analysis reported in the Journal of Clinical Oncology, Arrillaga-Romany et al found that single-agent ONC201 (dordaviprone), a first-in-class imipridone, showed activity in recurrent histone 3 (H3) K27M-mutant diffuse midline glioma.

As noted by the investigators, “H3 K27M–mutant diffuse midline glioma has a dismal prognosis with no established effective therapy beyond radiation.”

Study Details

The analysis included 46 adult patients and 4 pediatric patients from four clinical trials and one expanded-access protocol who received oral ONC201 monotherapy. The adult dose was 625 mg and the pediatric dose consisted of the adult dose scaled by body weight; doses were given once weekly or once every 3 weeks, depending on trial design. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria, a Karnofsky/Lansky performance score of ≥ 60, and had received radiation therapy with a washout of ≥ 90 days before the first ONC201 dose. Treatment continued until disease progression on RANO-HGG criteria or unacceptable toxicity. The primary outcome measure was overall response rate on RANO-HGG criteria.

Key Findings

Overall response rate on RANO-HGG criteria was 20.0% (95% confidence interval [CI] = 10.0%–33.7%). Median duration of response was 11.2 months (95% CI = 3.8 months to not reached). The median time to response was 8.3 months (range = 1.9–15.9 months). The disease control rate was 40%. Progression-free survival at 6 months was 35.1%. Median overall survival was 13.7 months, with rates at 12 and 24 months of 57.3% and 34.7%, respectively.

On combined RANO-HGG/low-grade glioma criteria, the overall response rate was 30.0% (95% CI = 17.9%–44.6%), and the disease control rate was 44%.

Corticosteroid dose reduction of ≥ 50% occurred in 7 (46.7%) of 15 evaluable patients. Performance score improved in 6 (20.6%) of 34 evaluable patients.

Grade 3 treatment-related adverse events occurred in 20% of patients, most commonly fatigue (10%). No grade 4 or 5 treatment-related adverse events were observed, and there were no discontinuations of ONC201 due to treatment-related adverse events. 

The investigators concluded, “ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M–mutant diffuse midline glioma.”

Isabel Arrillaga-Romany, MD, PhD, of Massachusetts General Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Chimerix, Inc. For full disclosures of the study authors, visit

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